The overall objective of the proposed studies is to define the mechanism by which the pulmonary consequences following burn injury are exacerbated by ethanol exposure. Nearly 100,000 people each year are admitted to hospitals due to burn injury and about half of those patients are reported to have been drinking ethanol. Ethanol exposure is not only a risk factor for the events that lead up to the fire-related accidents, but also leads to increased morbidity and mortality among burned patients. The lung is a critical organ, which is particularly sensitive to remote injury. This is, in part, because of the organ's extensive vascular bed and delicate alveolar architecture. Acute lung injury results from the overproduction of pro-inflammatory cytokines, which are generated both systemically and locally (in the lung) in response to injury, such as burn, and is amplified if alcohol is present at the time of injury. We hypothesize that the complications which arise in ethanol-exposed individuals who sustain burn injury are triggered by an overexuberant pulmonary inflammatory response. Herein, we propose to employ both in vivo and in vitro approaches to determine the mechanism(s) responsible for the increased magnitude and duration of pulmonary pathology in burn patients with or without prior ethanol consumption, which are paralleled in our well established murine model of acute ethanol exposure and burn injury. Additionally, we plan to define the roles of key pro-inflammatory and fibrogenic cytokines produced locally and systemically during the early and later post-burn period. We will examine the cellular sources of these factors to determine the extent to which the alveolar macrophage dictates the outcome by virtue of its cytokine production capacity. Finally, we plan to exploit our earlier observation that both systemic and organ-specific inflammatory responses seen after ethanol and burn injury can be ameliorated following systemic treatment with anti-inflammatory regimens, including 17?-estradiol. In the proposed studies, we will test whether this treatment will reduce the pulmonary inflammation seen in mice given the combined insult of ethanol exposure followed by burn injury, relative to either insult alone. It is anticipated that these studies will provide valuable information, which can be used to develop more efficacious therapies for the treatment of ethanol-exposed, burn patients. PUBLIC HEALTH RELEVANCE In the United States, injury remains the primary cause of death during the first four decades of life, outnumbering all other causes of death, including heart disease and cancer, and accounts for millions of disabling injuries per year and an annual cost of over $130 billion. The importance of ethanol as a complicating factor regarding injury is underscored by the finding that up to 50% of burn patients have detectable levels of ethanol in their circulation at the time of admission to the hospital. These patients, the majority of whom are not chronic alcoholics, but rather consumed alcohol on an acute or binge basis, suffer from increased morbidity and mortality compared with that of non-alcohol-consuming subjects with similar injuries.